Of ethyl acetoacetate with formaldehyde and ammonia

Synthesis of heterocycles. The first step of a procedure for the synthetic preparation of 2,6-dimethylpyridine (2,6-lutidine) involves condensation of 2 moles of ethyl acetoacetate with 1 mole each of formaldehyde (as formalin) and ammonia to produce the 1,4-dihydropyridine (1). Oxidation with HNO3-H2SO4 to the pyridine (2), saponification (3), and decarboxylation gave 2,6-dimethylpyridine (4). 

For instance, condensation of ethyl acetoacetate, formaldehyde, and ammonia gives dihydropyridine 5.12 which is readily oxidised with nitric acid to give pyridine 5.13. Although the precise details of this multicomponent condensation are not known, a reasonable pathway is shown below. 

To 500 g. (3.85 moles) of freshly distilled ethyl acetoacetate in a i-l. flask set in ice and well cooled, are added 152 g. (2.0 moles) of 40 per cent aqueous formaldehyde solution and 20-25 drops of diethylamine. The flask and contents are kept cold for six hours and are then allowed to stand at room temperature for forty to forty-five hours. At the end of this time two layers are present, a lower oily layer and an upper aqueous layer. The layers are separated, and the aqueous layer is extracted with 50 cc. of ether. The ether solution is added to the oily layer, and the resulting solution is dried over 30 g. of calcium chloride. The ether is then removed by distillation on a steam bath. The residue, amounting to approximately 500 g., is diluted with an equal volume of alcohol and is thoroughly cooled in an ice bath. Ammonia is then passed into the mixture until the solution is saturated. This requires from four to eight hours, and during this time the flask is kept packed in ice. The ammoniacal alcoholic solution is allowed to stand at room temperature for forty to forty-five hours. Most of the alcohol is now evaporated the residue is cooled, and the solid i,4-dihydro-3,5-dicarbethoxy-2,6-dimethylpyridine is removed from the remaining alcohol on a suction filter. The dried ester melts at 175-180 and amounts to 4ro-435 g. (84-89 per cent of the theoretical amount). 

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